Gut Microbiota in Monozygotic Twins Discordant for Parkinson's Disease.

Differences in gut microbiota between Parkinson's disease patients and controls seem to depend on multiple-frequently unmeasured-confounders. Monozygotic twins offer a unique model for controlling several factors responsible for interpersonal variation in gut microbiota. Fecal samples from 20 monozygotic twin pairs (n = 40) discordant for Parkinson's disease were studied (metagenomic shotgun analysis). Paired data analysis detected minimal differences in bacterial taxa abundance at species level (Bacteroides pectinophilus [p = 0.037], Bifidobacterium pseudocatenulatum [p = 0.050], and Bifidobacterium catenulatum [p = 0.025]) and in predicted metabolic pathways (primary bile acid biosynthesis [p = 0.037]). Additional studies are warranted to understand the role of gut microbiota in the pathogenesis of Parkinson's disease. ANN NEUROL 2022;92:631-636.

Gut microbiota dysbiosis in Parkinson disease: A systematic review and pooled analysis.

BACKGROUND AND PURPOSE: The role of the gut microbiome in the pathogenesis of Parkinson disease (PD) is under intense investigation, and the results presented are still very heterogeneous. These discrepancies arise not only from the highly heterogeneous pathology of PD, but also from widely varying methodologies at all stages of the workflow, from sampling to final statistical analysis. The aim of the present work is to harmonize the workflow across studies to reduce the methodological heterogeneity and to perform a pooled analysis to account for other sources of heterogeneity. METHODS: We performed a systematic review to identify studies comparing the gut microbiota of PD patients to healthy controls. A workflow was designed to harmonize processing across all studies from bioinformatics processing to final statistical analysis using a Bayesian random-effects meta-analysis based on individual patient-level data. RESULTS: The results show that harmonizing workflows minimizes differences between statistical methods and reveals only a small set of taxa being associated with the pathogenesis of PD. Increased shares of the genera Akkermansia and Bifidobacterium and decreased shares of the genera Roseburia and Faecalibacterium were most characteristic for PD-associated microbiota. CONCLUSIONS: Our study summarizes evidence that reduced levels of butyrate-producing taxa in combination with possible degradation of the mucus layer by Akkermansia may promote intestinal inflammation and reduced permeability of the gut mucosal layer. This may allow potentially pathogenic metabolites to transit and enter the enteric nervous system.

Resting energy expenditure in Parkinson's disease patients under dopaminergic treatment.

Background: Weight homeostasis is complex in Parkinson's disease (PD) and body weight changes substantially throughout the course of the disease. We designed a case-control study to (i) investigate whether PD is associated with changes in resting energy expenditure (REE), (ii) to assess how accurately REE could be predicted for individuals with PD utilizing the equations constructed for healthy individuals, and (iii) to eventually construct a new equation.Materials & Methods: Measured REE (mREE) was compared between 122 PD patients and 122 gender and body mass index (BMI)-matched controls. The accuracy of estimated REE by 5 common equations (Harris/Benedict-1919, Roza/Shizgal-1984, Mifflin St. Jeor, WHO/FAO and aggregate formula) was investigated in PD using Bland-Altman analysis and reported as the frequency of accurate predictions (±10%). Concordance correlation coefficients (CCC) were also calculated. Then, we regressed a new REE equation - using gender, age, weight, height and Hoehn-Yahr stage - and validated it in an independent sample (N = 100).Results: No significant difference in mREE was recorded between the whole PD sample and healthy controls. However, mREE was increased in patients with BMI ≥ 30 kg/m2 and Hoehn-Yahr stage ≥ 3. Limited accuracy was present in the available REE equations (accurate prediction [±10%] frequency, <60% for all). For the new equation, the proportion of accurate prediction was 67.0% (overestimation, 24.0%) and CCC was 0.77.Conclusion: PD patients are not commonly characterized by an increase in REE. This is limited to patients suffering from obesity and more severe disease. Common REE equations appear to be inaccurate. The new predictive equation proposed in this study provided better REE estimates.

Clinical correlates of serum 25-hydroxyvitamin D in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. MATERIALS AND METHODS: We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls (N = 100) was included as a control group. RESULTS: PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure (P = .002) and vitamin D intake (P = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY, P = .035), worse clinical symptoms (UPDRS Part-III total score [P = .006] and dopaminergic [P = .033] and non-dopaminergic subscores [P = .001]) and greater global cognitive function impairment (P = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. CONCLUSION: : Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required.

COVID-19 in Parkinson's Disease Patients Living in Lombardy, Italy.

BACKGROUND: It is unknown whether patients with PD are at greater risk of COVID-19, what their risk factors are, and whether their clinical manifestations differ from the general population. OBJECTIVES: The study aimed to address all these issues. METHODS: In a case-controlled survey, we interviewed 1,486 PD patients attending a single tertiary center in Lombardy, Italy and 1,207 family members (controls). RESULTS: One hundred five (7.1%) and 92 controls (7.6%) were identified as COVID-19 cases. COVID-19 patients were younger, more likely to suffer from chronic obstructive pulmonary disease, to be obese, and vitamin D nonsupplemented than unaffected patients. Six patients (5.7%) and 7 family members (7.6%) died from COVID-19. Patients were less likely to report shortness of breath and require hospitalization. CONCLUSIONS: In an unselected large cohort of nonadvanced PD patients, COVID-19 risk and mortality did not differ from the general population, but symptoms appeared to be milder. The possible protective role of vitamin D supplementation warrants future studies. © 2020 International Parkinson and Movement Disorder Society.

Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism.

BACKGROUND: Although several studies have suggested that abnormalities in gut microbiota may play a critical role in the pathogenesis of PD, data are still extremely heterogeneous. METHODS: 16S gene ribosomal RNA sequencing was performed on fecal samples of 350 individuals, subdivided into idiopathic PD (n = 193, of whom 39 were drug naïve) stratified by disease duration, PSP (n = 22), MSA (n = 22), and healthy controls (HC; n = 113). Several confounders were taken into account, including dietary habits. RESULTS: Despite the fact that unadjusted comparison of PD and HC showed several differences in relative taxa abundances, the significant results were greatly reduced after adjusting for confounders. Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced. CONCLUSIONS: Gut microbiota may be an environmental modulator of the pathogenesis of PD and contribute to the interindividual variability of clinical features. Data are influenced by PD duration and several confounders that need to be taken into account in future studies. Prospective studies in de novo PD patients are needed to elucidate the net effect of dysbiosis on the progression of the disease. © 2018 International Parkinson and Movement Disorder Society.

Nutritional characterisation of Zambian Moringa oleifera: acceptability and safety of short-term daily supplementation in a group of malnourished girls.

In Zambia, chronic malnutrition still is one of the most common problem among children. To fight against malnutrition, the easiest short-term solution could be to combine specific types of food with affordable local plants. A large variety of natural food resources grow in Zambia, such as Moringa oleifera (MO), whose leaves are known for their health benefits, but are not consumed much by local populations. We analysed Zambian MO powder obtained from dried leaves and found that it contains large amounts of protein, minerals and vitamins, such as iron, calcium and carotenoids. These characteristics make MO a good and sustainable complementary solution to malnutrition. We also evaluated the acceptability and the safety of dietary supplementation with MO powder in malnourished children for 30 days. A daily dose of 14 g daily was safe and well accepted. Its regular use in the menu of local populations may be viable proposition.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.

Metformin use is associated with reduced mortality risk in diabetic patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) and type-2 diabetes (T2D) arguably share pathophysiologic mechanisms, resulting in a more severe phenotype and progression and diabetes is currently considered a risk factor of PD. Besides, research suggests antidiabetic therapies as potential disease-modifying strategies. The main aim was to assess the impact of a metformin-inclusive antidiabetic treatment on patient all-cause mortality. METHODS: A nested case-control prospective study including newly diagnosed PD patients reporting the onset of T2D within ±2 years from the onset of PD (n = 159) and matched (1:5; gender, year of PD onset and age at PD onset) non-diabetic cases (n = 795) followed until death or censoring. Patients on a metformin-inclusive treatment regimen were compared to those receiving other oral anti-diabetics (OADs). RESULTS: Among patients with T2D, 123 were treated with a drug regimen containing metformin (alone [65.0%] or in combination with other drugs [35.0%]) and 36 were prescribed other OADs. During a median PD duration of 96 months [IQR, 60-144], 171 patients died. Diabetes was not associated with reduced survival: fully-adjusted HR = 1.19 [95%CI, 0.81-1.76] (P = 0.37). After stratifying for T2D treatment, a metformin-inclusive regimen was not associated with increased risk of death (HR = 1.06 [95%CI, 0.61-1.84]; P = 0.83), while patients receiving other OADs had reduced survival (HR = 1.83 [95%CI, 1.01-3.32]; P = 0.034). CONCLUSIONS: Metformin use was not associated with increased risk of death in diabetic patients with PD reporting concomitant onset of the two diseases. Metformin appears to be a promising disease-modifying therapy given also the preclinical background, low cost and satisfactory safety and tolerability. Further studies are warranted to investigate its impact on disease progression.

Mucuna pruriens to treat Parkinson's disease in low-income countries: Recommendations and practical guidelines from the farmer to clinical trials. Paving the way for future use in clinical practice.

Parkinson's disease (PD) is a progressive and disabling neurodegenerative disease that rapidly worsens and results in premature mortality if left untreated. Although levodopa is the gold standard treatment for PD globally, its accessibility and affordability are severely limited in low- and middle-income countries worldwide. In this scenario, Mucuna pruriens (MP), a leguminous plant growing wild in tropical regions, emerges as a potential alternative or adjunct to levodopa-based medications due to its cost-effectiveness and global natural availability. Recent studies have demonstrated that MP can significantly ameliorate motor symptoms, although tolerability may vary. The proposition that MP could play a pivotal role in providing affordable and symptomatic relief for PD in low- and middle-income countries is grounded in its promising therapeutic profile, yet caution is warranted until more comprehensive data on the long-term safety and efficacy of MP become available. This manuscript summarizes the knowledge gained about MP by the authors, focusing on how to cultivate, store, and provide it to patients in the safest and most effective way in clinical trials. We aim to increase clinical trials investigating its safety and efficacy in PD, before promoting individual use of MP on a global scale, particularly in countries where availability and affordability of levodopa-based medications is still limited.

Nutritional risk and gastrointestinal dysautonomia symptoms in Parkinson's disease outpatients hospitalised on a scheduled basis.

Dysautonomia symptoms of nutritional interest may often occur in Parkinson's disease (PD), but the role played in affecting the risk of malnutrition still needs to be clarified. A total of 208 consecutive PD outpatients hospitalised on a scheduled basis were assessed for nutritional risk by the Malnutrition Universal Screening Tool. Presence of dysautonomia symptoms (dysphagia, sialorrhoea and constipation) was investigated using clinical rating scales. In our population, prevalence of nutritional risk was 17·2 (95 % CI 12·1, 24·0) % and relied mainly on unintentional weight loss. Sialorrhoea, dysphagia, dysphagia to liquids and constipation were observed in 10·6, 11·0, 14·4 and 59·6 % of the patients, respectively. Nutritional risk was independently associated with the number of dysautonomia symptoms (OR 1·39 (95 % CI 1·00, 1·96); P= 0·048) but not with single symptoms. An independent association was also found with the severity of motor symptoms (Hoehn-Yahr stage, OR 1·48 (95 % CI 1·00, 2·55); P= 0·049) and levodopa dose (OR 1·16 (95 % CI 1·04, 1·31) mg/kg per d; P= 0·009). Nutritional risk in PD outpatients appears to depend mainly on dysautonomic syndrome, disease severity and levodopa dosage. Implications for outcome deserve further investigation. The assessment of nutritional status and of gastrointestinal dysautonomia symptoms should be part of the routine work-up of a PD patient.

Onset and mortality of Parkinson's disease in relation to type II diabetes.

OBJECTIVES: There is growing evidence that Parkinson's disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific treatments, are still unclear. We evaluated the effect of T2D and antidiabetic treatment on age at PD onset and on all-cause mortality. RESEARCH DESIGN AND METHODS: The standardized rate of T2D was calculated for PD patients using the direct method and compared with subjects with essential tremor (ET) and the general Italian population. Age at onset and survival were also compared between patients without T2D (PD-noT2D), patients who developed T2D before PD onset (PD-preT2D) and patients who developed T2D after PD onset (PD-postT2D). RESULTS: We designed a retrospective and prospective study. The T2D standardized ratio of PD (N = 8380) and ET (N = 1032) patients was 3.8% and 6.1%, respectively, while in the Italian general population, the overall prevalence was 5.3%. In PD-preT2D patients, on antidiabetic treatment, the onset of PD was associated with a + 6.2 year delay (p < 0.001) while no difference was observed in PD-postT2D. Occurrence of T2D before PD onset negatively affected prognosis (adjusted hazard ratio = 1.64 [95% CI 1.33-2.02]; p < 0.001), while no effect on survival was found in PD-postT2D subjects (hazard ratio = 0.86, [95% CI 0.53-1.39]; p = 0.54). CONCLUSIONS: T2D, treated with any antidiabetic therapy before PD, is associated with a delay in its onset. Duration of diabetes increases mortality in PD-preT2D, but not in PD-postT2D. These findings prompt further studies on antidiabetic drugs as a potential disease-modifying therapy for PD.

Vitamin D Status and Parkinson's Disease.

Parkinson's disease (PD) is a complex and progressive neurodegenerative disease, characterized by resting tremor, rigidity, slowness of movement, and postural instability. Furthermore, PD is associated with a wide spectrum of non-motor symptoms that add to overall disability. In recent years, some investigations, from basic science to clinical applications, have focused on the role of vitamin D in PD, often with controversial findings. Vitamin D has widespread effects on several biological processes in the central nervous system, including neurotransmission in dopaminergic neural circuits. Various studies have recorded lower levels of vitamin D in PD patients than in healthy controls. Low vitamin D status has also been correlated with the risk for PD and motor severity, whereas less is known about the effects vitamin D has on cognitive function and other non-motor symptoms. This review aims to better characterize the correlation between vitamin D and PD, clarify the role of vitamin D in PD prevention and treatment, and discuss avenues for future research in this field.

Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease.

INTRODUCTION: Astrocytes are involved in Parkinson's disease (PD) where they could contribute to α-Synuclein pathology but also to neuroprotection via α-Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α-Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients. METHODS: The expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α-Synuclein oligomers in human astrocytes. RESULTS: We found that vitamin D-activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α-Synuclein oligomers and are associated with Lewy body negative neurons. CONCLUSION: The presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.

Awareness and knowledge about weight status and management: results from the 1 d sensitization campaign 'Obesity Day' in northern Italy.

OBJECTIVE: To evaluate the awareness and knowledge about weight status and its management. DESIGN: A 1 d cross-sectional survey. Basic anthropometric assessments (weight, height, BMI and waist circumference) and a self-administered questionnaire were considered. SETTING: Nineteen Clinical Nutrition or Endocrinology and Metabolic Disorders Units or Dietetics Services in the Italian region of Lombardy. SUBJECTS: All adults attending the 'Obesity Day' initiative. RESULTS: A total of 914 participants (605 female and 309 male) were recruited. Although most of the participants (83·5 %) considered obesity to be a disease, 38·5 % were likely to misperceive their weight status. In particular, 38·8 % of normal-weight adults believed themselves to be overweight, whereas 71·1 % and 37·5 % of classes I and II/III obese adults classified themselves as being overweight and mildly obese, respectively. However, most of the overweight (90·2 %), mildly (96·8 %) and moderately/severely obese adults (99·1 %) recognized the need to lose weight. In all, 37·8 % of the sample underestimated the role of physical activity in weight management. Interestingly, only 17·2 % of dieters (previous or current) declared being advised by their doctor to lose weight. Multivariate models revealed that higher age, low education and higher BMI were important determinants of poor weight control and management. In addition, previous dieting appeared not to provide better knowledge, whereas the role of physical activity was recognized mainly by those practising it. CONCLUSIONS: The present study suggests that in Italy knowledge about weight management should be improved not only in the general population but also among health-care professionals. To confirm this finding, there is now the rationale for a nationally representative survey. New educational programmes can be designed on the basis of the information collected.

Does Gut Microbiota Influence the Course of Parkinson's Disease? A 3-Year Prospective Exploratory Study in de novo Patients.

BACKGROUND: Although abnormalities in gut microbiota are hypothesized to influence the pathogenesis and clinical phenotype of Parkinson's disease (PD), prospective studies on de novo patients are lacking. OBJECTIVE: To preliminarily investigate whether gut microbiota in early untreated PD may predict motor and non-motor features progression over a 3-year period. METHODS: 16S ribosomal RNA gene amplicons were sequenced on fecal samples of 39 de novo PD patients. Multiple confounders were taken into account, including dietary habits. Motor and non-motor symptoms were assessed using validated scales at baseline and followed-up yearly for 3 years. At last follow-up, a detailed neuropsychological assessment was additionally performed. A general linear model for repeated measurements- adjusted by dopaminergic therapy at follow-up- was used to investigate the relationship between bacterial taxa abundance at baseline (stratified by the median of distribution at baseline) and outcome variables. RESULTS: Twenty-five patients were included (11 refused, 2 lost at follow-up, 1 died). Lower abundance of Roseburia (Firmicutes phylum) at baseline was associated with worse evolution of motor, non-motor and cognitive functions at 3-year follow-up. Similarly, lower abundance of Ruminococcaceae and Actinobacteria at baseline was associated with faster worsening of global cognitive functions. At follow-up, frontal lobe functions were the features most robustly associated with baseline microbial abnormalities. CONCLUSION: In the present exploratory study on de novo PD, we found an association between abnormal distribution of specific bacterial taxa and the progression of motor and non-motor features over a 3-year period. This proof-of-principle study supports the design of a larger observational study aiming to determine whether these differences survive multiple-comparison correction and define microbiota-specific subgroups suitable for therapeutic targeting.

Low-protein and protein-redistribution diets for Parkinson's disease patients with motor fluctuations: a systematic review.

The American Academy of Neurology suggests advising the redistribution of daily protein meal content to every Parkinson's disease (PD) patient with motor fluctuations during levodopa treatment. However, no comprehensive evaluation of this complementary therapy has been performed. A systematic review of intervention studies investigating the neurologic outcome of low-protein (<0.8 g/kg of ideal weight/day) and protein-redistribution diets in patients with PD experiencing motor fluctuations during levodopa treatment. All studies (uncontrolled or randomized) investigating a low-protein and/or a protein-redistribution diet (LPD and PRD) and involving patients with PD with motor fluctuations were included, provided that sufficient information on dietary protein content and neurologic outcome measures was available. We identified 16 eligible studies, but they were markedly heterogeneous. There was not enough evidence to support the use of LPD. Response to PRD seemed very good. Acceptability appeared high upon introduction, but it seemed to progressively decrease over time. On average, PRD resulted in improved motor function, but also complications occurred. At the beginning, drop-outs were due to levodopa side effects rather than unsatisfactory benefits. Long-term adherence was more affected by changes in dietary habits than by diet-related side effects. Efficacy and benefits appeared to be higher when the intervention was proposed to subjects in the early stages of PD. PRD can be safely advised to fluctuating patients with PD, but those in whom benefits override the possible inconveniences still need to be identified. The long-term effects of PRD on nutritional status should be evaluated and true effectiveness in clinical practice should be reassessed, given the changes in levodopa formulations and the introduction of several adjuvants (levodopa degradation inhibitors and/or dopamine agonists).

Controlled-protein dietary regimens for Parkinson's disease.

Continuous levodopa replacement still is the most efficacious treatment for patients with Parkinson's disease. Unfortunately, the neutral aromatic amino acids contained in dietary proteins may compete with this drug for intestinal absorption and transport across the blood-brain barrier, thus limiting its efficacy and being responsible for the occurrence of motor fluctuations. Current guidelines recommend low-protein dietary regimens with protein redistribution, as shifting protein intake to the evening has proved to ameliorate the response to levodopa. However, adherence to this dietary regimen does not seem to be satisfactory and response is variable. Recent studies have shown that low-protein products designed for chronic renal failure patients are safe, tasty, well-tolerated and useful in improving both adherence to low-protein dietary regimens and levodopa-related motor fluctuations. However, there still is the need to define the selection criteria for the patients who may benefit the most from adherence to this regimen.